This subproject has two major foci; the development of compounds as pharmacotherapies for opiate addiction and the development of delta opioid drugs for use in allodynia / hyperalgesia and in depression. We have previously identified cinnamoylamide-morphinones and codeinones as lead compounds in the search for pharmacotherapies for opiate abuse. Several compounds in this class provide for mu-agonism followed by long-lasting mu-antagonism that will likely prevent drug-seeking behavior for long periods. The initial agonism provides for patient compliance. However, neither the mechanism behind the switch from agonism to antagonism nor the reasons behind the long-lasting antagonism are known. Aim 1 will use in vitro pharmacology and molecular modeling together with medicinal chemistry to understand and improve on our current lead compounds. This will be complemented by Aim 4 that provides a search for structurally novel agents through the auspices of the College on Problems of Drug Dependence, and for the development of in vitro assays more predictive of in vivo behavior. We will use in vivo and in vitro methodologies to build on findings on the usefulness of non-peptide delta ligands in hyperalgesia and allodynia and as potential antidepressant agents. Delta agonists are potentially useful systemically active agents for these conditions but suffer from the disadvantage of causing seizures and a very rapid tolerance development. Aim 3 will address whether seizures, antinociceptive activity and potential antidepressant activity can be separated, for example by differential efficacy or through activation of different receptor subtypes. Potential antidepressant activity of the compounds will be determined using the forced swim test in rats. If we are to be successful in our search for novel therapies it is necessary to continue to ask questions regarding mechanisms of opioid action. Under aim 2 we will study the relationships of opioid receptors to G proteins and the mechanisms of activation of intracellular messengers. This will involve study of cross-talk between receptors in the light of recent discovery of G protein coupled receptor oligomerization, and the basis of intrinsic activity of opioid ligands from full agonism, through to inverse agonism.